The proposed studies will develop methods for treating HIV-1 infections by the ex vivo application of antisense therapy. Toward this end, the investigators have developed multitargeting DNA constructs that impart a stable cellular resistance to HIV-1. These multitargeting constructs provide for the simultaneous expression of antisense RNA transcripts directed against target sequences in tar, the tat/rev exon and the tat/rev splice acceptor sequence. As a further measure to maximize antisense effectiveness, each antisense sequence has been incorporated into a U1 snRNA transcript in order to provide stability, efficient expression and nuclear localization. As an approach to the development of ex vivo procedures for clinical studies, the effectiveness of multitargeting U1/HIV antisense in protecting peripheral blood lymphocytes from HIV-1 challenge will be tested. Successful protection of PBLs will provide the basis for progress in therapeutic development for ex vivo therapy wherein the multitargeting U1/HIV antisense construct will be inserted into bone marrow stem cells or into CD4+ cells. PROPOSED COMMERCIAL APPLICATION: Not available.